U.S. patent application number 14/190618 was filed with the patent office on 2014-06-26 for solid pharmaceutical dosage form.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Laman Alani, Gunther Berndl, Joerg Breitenbach, Soumojeet Ghosh, Bernd Liepold, Ulrich Reinhold, Joerg Rosenberg.
Application Number | 20140179721 14/190618 |
Document ID | / |
Family ID | 34526332 |
Filed Date | 2014-06-26 |
United States Patent
Application |
20140179721 |
Kind Code |
A1 |
Rosenberg; Joerg ; et
al. |
June 26, 2014 |
SOLID PHARMACEUTICAL DOSAGE FORM
Abstract
A solid pharmaceutical dosage form providing improved oral
bioavailability is disclosed for inhibitors of HIV protease. In
particular, the dosage form comprises a solid dispersion of at
least one HIV protease inhibitor and at least one pharmaceutically
acceptable water-soluble polymer and at least one pharmaceutically
acceptable surfactant, said pharmaceutically acceptable
water-soluble polymer having a Tg of at least about 5.degree. C.
Preferably, the pharmaceutically acceptable surfactant has an HLB
value of from about 4 to about 10.
Inventors: |
Rosenberg; Joerg;
(Ellerstadt, DE) ; Reinhold; Ulrich; (Heidelberg,
DE) ; Liepold; Bernd; (Dossenheim, DE) ;
Berndl; Gunther; (Herxheim, DE) ; Breitenbach;
Joerg; (Mannheim, DE) ; Alani; Laman; (Foster
City, CA) ; Ghosh; Soumojeet; (Lansdale, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
34526332 |
Appl. No.: |
14/190618 |
Filed: |
February 26, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13674799 |
Nov 12, 2012 |
8691878 |
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14190618 |
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12880781 |
Sep 13, 2010 |
8309613 |
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13674799 |
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10925442 |
Aug 25, 2004 |
8025899 |
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12880781 |
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60498412 |
Aug 28, 2003 |
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Current U.S.
Class: |
514/274 ;
514/365 |
Current CPC
Class: |
A61K 31/513 20130101;
A61K 31/427 20130101; A61K 9/1635 20130101; A61K 9/10 20130101;
A61K 9/2095 20130101; A61K 47/32 20130101; A61K 9/2077 20130101;
Y10S 514/937 20130101; A61K 9/1617 20130101; A61K 47/26 20130101;
A61P 31/18 20180101 |
Class at
Publication: |
514/274 ;
514/365 |
International
Class: |
A61K 47/32 20060101
A61K047/32; A61K 47/26 20060101 A61K047/26; A61K 31/513 20060101
A61K031/513; A61K 31/427 20060101 A61K031/427 |
Claims
1. A solid pharmaceutical dosage form comprising a solid
dispersion, wherein said solid dispersion comprises at least one
HIV protease inhibitor, wherein said at least one HIV protease
inhibitor comprises ritonavir; at least one pharmaceutically
acceptable surfactant having an HLB value of from about 4 to about
10 or a combination of pharmaceutically acceptable surfactants
having an HLB value of from about 4 to about 10; and at least one
pharmaceutically acceptable water-soluble polymer having a Tg of at
least about 50.degree. C. or a combination of pharmaceutically
acceptable water-soluble polymers having a Tg of at least about
50.degree. C.
2. The dosage form of claim 1, wherein said solid dispersion is a
solid solution or a glassy solution.
3. The dosage form of claim 2, wherein said solid dispersion is a
solid solution.
4. The dosage form of claim 1, wherein said surfactant is from
about 2 to about 20% by weight of the total dosage form.
5. The dosage form of claim 1, wherein said solid dispersion
comprises a combination of pharmaceutically acceptable surfactants
having an HLB value of from about 4 to about 10.
6. The dosage form of claim 1, wherein said surfactant is a
sorbitan fatty acid ester.
7. The dosage form of claim 6, wherein said surfactant is sorbitan
monolaurate.
8. The dosage form of claim 1, wherein said water-soluble polymer
is from about 50 to about 85% by weight of the total dosage
form.
9. The dosage form of claim 1, wherein said water-soluble polymer
has a Tg of from about 80 to about 180.degree. C.
10. The dosage form of claim 1, wherein said solid dispersion
comprises a combination of pharmaceutically acceptable
water-soluble polymers having a Tg of at least about 50.degree.
C.
11. The dosage form of claim 1, wherein said pharmaceutically
acceptable water-soluble polymer is selected from the group
consisting of homopolymer of N-vinyl lactam, copolymer of N-vinyl
lactam, cellulose ester, cellulose ether, polyalkylene oxide,
polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol,
vinyl acetate polymer, oligosaccharide, and polysaccharide.
12. The dosage form of claim 11, wherein said pharmaceutically
acceptable water-soluble polymer is selected from the group
consisting of homopolymer of N-vinyl pyrrolidone, copolymer of
N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl
acetate, copolymer of N-vinyl pyrrolidone and vinyl propionate,
polyvinylpyrrolidone, methylcellulose, ethylcellulose,
hydloxyalkylcelluloses, hydloxypropylcellulose,
hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose
phthalate, cellulose succinate, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate,
hydroxypropylmethylcellulose acetate succinate, polyethylene oxide,
polypropylene oxide, copolymer of ethylene oxide and propylene
oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic
acid/methyl methacrylate copolymer, butyl
methacrylate/2-dimethylaminoethyl methacrylate copolymer,
poly(hydloxyalkyl acrylate), poly(hydloxyalkyl methacrylate),
copolymer of vinyl acetate and crotonic acid, partially hydlolyzed
polyvinyl acetate, carrageenan, galactomannan, and xanthan gum.
13. The dosage form of claim 12, wherein said water-soluble polymer
is a copolymer of N-vinyl pyrrolidone and vinyl acetate.
14. The dosage form of claim 13, wherein said at least one
pharmaceutically acceptable water-soluble polymer comprises
copovidone.
15. The dosage form of claim 1, wherein said surfactant is from
about 2 to about 20% by weight of the total dosage form, and said
water-soluble polymer is from about 50 to about 85% by weight of
the total dosage form.
16. The dosage form of claim 1, wherein said water-soluble polymer
is a copolymer of N-vinyl pyrrolidone and vinyl acetate, and said
surfactant is a sorbitan fatty acid ester.
17. The dosage form of claim 1, wherein said water-soluble polymer
is copovidone, and said surfactant is sorbitan monolaurate.
18. The dosage form of claim 1, wherein said dosage form is
prepared by a process comprising solidifying a melt comprising
ritonavir, said at least one pharmaceutically acceptable
surfactant, and said at least one pharmaceutically acceptable
water-soluble polymer.
19. The dosage form of claim 1, wherein said solid dispersion is
prepared by melt-extrusion, spray-drying or solution
evaporation.
20. The dosage form of claim 1 which contains, upon storage for 6
weeks at 40.degree. C. and 75% humidity, at least 98% of the
initial content of ritonavir.
21. The dosage form of claim 1, wherein said dosage form improves
ritonavir bioavailability in dogs as compared to the same dosage
form without surfactant having an HLB value of from 4 to 10.
22. The dosage form of claim 1, wherein said dosage form has a
dose-adjusted AUC, in dogs under non-fasting conditions, of
ritonavir plasma concentration of at least 9 .mu.g h/ml/100 mg.
23. The dosage form of claim 1, wherein the at least one HIV
protease inhibitor further comprises lopinavir.
24. The dosage form of claim 23, wherein said dosage form improves
ritonavir and lopinavir bioavailability in dogs as compared to the
same dosage form without surfactant having an HLB value of from 4
to 10.
25. The dosage form of claim 23, wherein said dosage form has a
dose-adjusted AUC, in dogs under non-fasting conditions, of
ritonavir plasma concentration of at least 9 .mu.g h/ml/100 mg, and
a dose-adjusted AUC, in dogs under non-fasting conditions, of
lopinavir plasma concentration of at least 20 .mu.g h/ml/100 mg.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/674,799, filed on Nov. 12, 2012, which is a
continuation of U.S. patent application Ser. No. 12/880,781, filed
on Sep. 13, 2010, which is a divisional of U.S. patent application
Ser. No. 10/925,442, filed on Aug. 25, 2004, which claims priority
from U.S. Provisional Application Ser. No. 60/498,412, filed on
Aug. 28, 2003, both of which are incorporated herein by reference
in their entireties.
[0002] The present invention is directed to a solid pharmaceutical
dosage form comprising at least one HIV protease inhibitor, and a
process for preparing same.
[0003] The virus causing acquired immunodeficiency syndrome (AIDS)
is known by different names, including T-lymphocyte virus III
(HTLV-III) or lymphadenopathy-associated virus (LAV) or
AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up
until now, two distinct families have been identified, i.e., HIV-1
and HIV-2.
[0004] One of the critical pathways in a retroviral life cycle is
the processing of polyprotein precursors by aspartic protease. For
instance with the HIV virus the gag-pol protein is processed by HIV
protease. The correct processing of the precursor polyproteins by
the aspartic protease is required for the assembly of infectious
virions, thus making the aspartic protease an attractive target for
antiviral therapy. In particular for HIV treatment, the HIV
protease is an attractive target.
[0005] A measure of the potential usefulness of an oral dosage form
of a pharmaceutical agent is the bioavailability observed after
oral administration of the dosage form. Various factors can affect
the bioavailability of a drug when administered orally. These
factors include aqueous solubility, drug absorption throughout the
gastrointestinal tract, dosage strength and first pass effect.
Aqueous solubility is one of the most important of these factors.
Unfortunately, HIV protease inhibiting compounds typically are
characterized by having poor aqueous solubility.
[0006] For a variety of reasons, such as patient compliance and
taste masking, a solid dosage form is usually preferred over a
liquid dosage form. In most instances however, oral solid dosage
forms of a drug provide a lower bioavailability than oral solutions
of the drug.
[0007] There have been attempts to improve the bioavailability
provided by solid dosage forms by forming solid solutions of the
drug. The term "solid solution" defines a system in a solid state
wherein the drug is molecularly dispersed throughout a matrix such
that the system is chemically and physically uniform or homogenous
throughout. Solid solutions are preferred physical systems because
the components therein readily form liquid solutions when contacted
with a liquid medium such as gastric juice. The ease of dissolution
may be attributed at least in part to the fact that the energy
required for dissolution of the components from a solid solution is
less than that required for the dissolution of the components from
a crystalline or microcrystalline solid phase. If, however, the
drug absorption in the gastrointestinal tract is slow the drug
released from the solid solution may result in a high
supersaturation and precipitate in the aqueous fluids of the
gastrointestinal tract.
[0008] There is a continuing need for the development of improved
oral solid dosage forms for HIV protease inhibitors which have
suitable oral bioavailability and stability and which do not
necessitate high vehicle volumes.
[0009] The present invention provides a solid pharmaceutical dosage
form comprising a solid dispersion of at least one HIV protease
inhibitor in at least one pharmaceutically acceptable water-soluble
polymer and at least one pharmaceutically acceptable surfactant. In
one embodiment, the pharmaceutically acceptable water-soluble
polymer has a glass transition temperature (Tg) of at least about
50.degree. C.
[0010] The term "solid dispersion" defines a system in a solid
state (as opposed to a liquid or gaseous state) comprising at least
two components, wherein one component is dispersed evenly
throughout the other component or components. For example, the
active ingredient or combination of active ingredients is dispersed
in a matrix comprised of the pharmaceutically acceptable
water-soluble polymer(s) and pharmaceutically acceptable
surfactant(s). The term "solid dispersion" encompasses systems
having small particles, typically of less than 1 .mu.m in diameter,
of one phase dispersed in another phase. When said dispersion of
the components is such that the system is chemically and physically
uniform or homogenous throughout or consists of one phase (as
defined in thermodynamics), such a solid dispersion will be called
a "solid solution" or a "glassy solution". A glassy solution is a
homogeneous, glassy system in which a solute is dissolved in a
glassy solvent. Glassy solutions and solid solutions of HIV
protease inhibitors are preferred physical systems. These systems
do not contain any significant amounts of active ingredients in
their crystalline or microcrystalline state, as evidenced by
thermal analysis (DSC) or X-ray diffraction analysis (WAXS).
[0011] In one embodiment of the present invention, the
pharmaceutical dosage form is comprising from about 5 to about 30%
by weight of the total dosage form (preferably from about 10 to
about 25% by weight of the total dosage form) of an HIV protease
inhibitor or a combination of HIV protease inhibitors, from about
50 to about 85% by weight of the total dosage form (preferably from
about 60 to about 80% by weight of the total dosage form) of a
water-soluble polymer (or any combination of such polymers), from
about 2 to about 20% by weight of the total dosage form (preferably
from about 3 to about 15% by weight of the total dosage form) of
the surfactant (or combination of surfactants), and from about 0 to
about 15% by weight of the total dosage form of additives.
[0012] HIV protease inhibiting compounds suitable for use in the
present invention include for example, but are not limited thereto:
[0013]
(2S,3S,5S)-5-(N--((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carb-
onyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,-
6-diphenyl-3hydroxyhexane (ritonavir); [0014]
(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahyd-
ro-pyrimid-2-onyl)-3-methylbutanoyl]-amino-1,6-diphenylhexane
(ABT-378; lopinavir); [0015]
N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-p-
yridyl-methyl)-2(S)--N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide(in-
dinavir); [0016]
N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbo-
nyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide
(saquinavir); [0017]
5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-
-Phe-morpholin-4-ylamide; [0018]
1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)3-amino-2-hydroxy-4-butanoyl-
-1,3-thiazolidine-4t-butylamide; [0019]
5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-bu-
tanoyl-1,3-thiazolidine-4-tbutylamide; [0020]
[1S-[1R--(R--),2S*])--N.sup.1[3-[[[(1,1-dimethylethyl)amino]carbonyl](2-m-
ethylpropyl)amino]-2hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbon-
yl)amino]-butanediamide; [0021] amprenavir (VX-478); DMP-323;
DMP-450; AG1343 (nelfinavir); [0022] atazanavir (BMS 232,632);
[0023] tipranavir, [0024] palinavir; [0025] TMC-114; [0026]
RO033-4649; [0027] fosamprenavir (GW433908); [0028] P-1946; [0029]
BMS 186,318; SC-55389a; BILA 1096 BS; and U-140690, or combinations
thereof.
[0030] In one embodiment, ritonavir (Abbott Laboratories, Abbott
Park, Ill., USA) is an HIV protease inhibitor which may be
formulated into the dosage form of the invention. This and other
compounds as well as methods for preparing same are disclosed in
U.S. Pat. Nos. 5,542,206 and 5,648,497, the disclosures of which
are herein incorporated by reference. In a further embodiment, the
present invention provides a dosage form wherein said HIV protease
inhibitor is ritonavir or a combination of ritonavir and at least
one other HIV protease inhibitor, the dosage form showing a
dose-adjusted AUC of ritonavir plasma concentration in dogs of at
least about 9 .mu.gh/ml/100 mg.
[0031] In another embodiment, lopinavir (Abbott Laboratories,
Abbott Park, Ill., USA) is an HIV protease inhibitor which may be
formulated into the dosage form of the invention. This and other
compounds, as well as methods for preparing same, are identified in
U.S. Pat. No. 5,914,332, the disclosure of which is herein
incorporated by reference. In a further embodiment, the present
invention provides a dosage form wherein said HIV protease
inhibitor is lopinavir or a combination of lopinavir and at least
one other HIV protease inhibitor, the dosage form showing a
dose-adjusted AUC of lopinavir plasma concentration in dogs of at
least about 20 .mu.gh/ml/100 mg (preferably at least about 22.5
.mu.gh/ml/100 mg, most preferred at least about 35 .mu.gh/ml/100
mg).
[0032] In yet another embodiment, nelfinavir mesylate (marketed
under the tradename Viracept by Agouron Pharmaceuticals, Inc. in La
Jolla, Calif.) is an HIV protease inhibitor which may be formulated
into the dosage form of the invention.
[0033] The dosage forms of the present invention exhibit a release
and absorption behaviour that is characterized by high attainable
AUC, high attainable C.sub.max (maximum plasma concentration), and
low T.sub.max (time to reach maximum plasma concentration).
[0034] In still another embodiment, the present invention provides
a dosage form wherein said HIV protease inhibitor is a combination
of ritonavir and lopinavir, the dosage form showing a dose-adjusted
AUC of ritonavir plasma concentration in dogs of at least about 9
.mu.gh/ml/100 mg and a dose-adjusted AUC of lopinavir plasma
concentration of at least about 20 .mu.gh/ml/100 mg (preferably at
least about 22.5 .mu.gh/ml/100 mg, most preferred at least about 35
.mu.gh/ml/100 mg).
[0035] The term "AUC" means "Area Under the Curve" and is used in
its normal meaning, i.e. as the area under the plasma
concentration-time curve from 0 to 24 hours, where the dosage form
has been administered orally to dogs (beagle) under non-fasting
conditions. "Non-fasting condition" means that the dogs receive a
nutritionally balanced daily ration during the pre-test period and
the whole test period. The AUC has units of concentration times
time. Once the experimental concentration-time points have been
determined, the AUC may conveniently be calculated, e.g. by a
computer program or by the trapezoidal method. All AUC data herein
were dose adjusted to the 100 mg dose level. For the purposes
herein, the AUC is determined within a dose range where the AUC
increases proportionally with dose. Administration of 50 mg
ritonavir or 200 mg lopinavir, respectively, to dogs is considered
suitable for determining the AUC values as used herein.
[0036] The dosage forms according to the invention are
characterized by an excellent stability and, in particular, exhibit
high resistance against recrystallization or decomposition of the
active ingredient(s). Thus, upon storage for 6 weeks at 40.degree.
C. and 75% humidity (e.g., when kept in high density polyethylene
(HDPE) bottles without desiccant), the dosage forms according to
the present invention usually do not exhibit any sign of
crystallinity (as evidenced by DSC or WAXS analysis) and contain at
least about 98% of the initial active ingredient content (as
evidenced by HPLC analysis).
[0037] The term "pharmaceutically acceptable surfactant" as used
herein refers to a pharma-ceutically acceptable non-ionic
surfactant. In one embodiment, the dosage form is comprising at
least one surfactant having an hydrophilic lipophilic balance (HLB)
value of from about 4 to about 10, preferably from about 7 to about
9. The HLB system (Fiedler, H. B., Encyclopedia of Excipients,
5.sup.th ed., Aulendorf: ECV-Editio-Cantor-Verlag (2002))
attributes numeric values to surfactants, with lipophilic
substances receiving lower HLB values and hydrophilic substances
receiving higher HLB values. Surfactants having an HLB value of
from about 4 to about 10 suitable for use in the present invention
include for example, but are not limited thereto:
[0038] polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3)
lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2)
stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene
alkylaryl ethers, e.g. polyoxyethylene (2) nonylphenyl ether,
polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4)
nonylphenyl ether, polyoxyethylene (3) octylphenyl ether;
[0039] polyethylene glycol fatty acid esters, e.g. PEG-200
monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400
dilaurate, PEG-300 distearate, PEG-300 dioleate;
[0040] alkylene glycol fatty acid mono esters, e.g. propylene
glycol monolaurate (Lauroglycol.RTM.);
[0041] sucrose fatty acid esters, e.g. sucrose monostearate,
sucrose distearate, sucrose monolaurate, sucrose dilaurate; or
[0042] sorbitan fatty acid mono esters such as sorbitan mono
laurate (Span.RTM. 20), sorbitan monooleate, sorbitan monopalmitate
(Span.RTM. 40), or sorbitan stearate, or
[0043] mixtures of one or more thereof.
[0044] The sorbitan mono fatty acid esters are preferred, with
sorbitan mono laurate and sorbitan monopalmitate being particularly
preferred.
[0045] Besides the surfactant having an HLB value of from about 4
to about 10, the dosage form may comprise additional
pharmaceutically acceptable surfactants such as polyoxyethylene
castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate
or polyoxyl 35 castor oil (Cremophor.RTM. EL; BASF Corp.) or
polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40
hydrogenated castor oil (Cremophor.RTM. RH40) or polyethylenglycol
60 hydrogenated castor oil (Cremophor.RTM. RH 60); or block
copolymers of ethylene oxide and propylene oxide, also known as
polyoxyethylene polyoxypropylene block copolymers or
polyoxyethylene polypropyleneglycol, such as Poloxamer.RTM. 124,
Poloxamer.RTM. 188, Poloxamer.RTM. 237, Poloxamer.RTM. 388,
Poloxamer.RTM. 407 (BASF Wyandotte Corp.); or a mono fatty acid
ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20)
sorbitan monooleate (Tween.RTM. 80), polyoxyethylene (20) sorbitan
monostearate (Tween.RTM. 60), polyoxyethylene (20) sorbitan
monopalmitate (Tween.RTM. 40), polyoxyethylene (20) sorbitan
monolaurate (Tween.RTM. 20).
[0046] Where such additional surfactants are used, the surfactant
having an HLB value of from about 4 to about 10 generally accounts
for at least about 50% by weight, preferably at least about 60% by
weight, of the total amount of surfactant used.
[0047] The water-soluble polymer employed in the present invention
has a Tg of at least about 50.degree. C., preferably at least about
60.degree. C., most preferred from about 80.degree. C. to about
180.degree. C. Methods for determining Tg values of the organic
polymers are described in "Introduction to Physical Polymer
Science", 2nd Edition by L. H. Sperling, published by John Wiley
& Sons, Inc., 1992. The Tg value can be calculated as the
weighted sum of the Tg values for homopolymers derived from each of
the individual monomers, i.e., that make up the polymer:
Tg=.SIGMA.W.sub.iX.sub.i where W is the weight percent of monomer i
in the organic polymer, and X is the Tg value for the homopolymer
derived from monomer i. Tg values for the homopolymers may be taken
from "Polymer Handbook", 2nd Edition by J. Brandrup and E. H.
Immergut, Editors, published by John Wiley & Sons, Inc.,
1975.
[0048] Water-soluble polymers having a Tg as defined above allow
for the preparation of solid dispersions that are mechanically
stable and, within ordinary temperature ranges, sufficiently
temperature stable so that the solid dispersions may be used as
dosage forms without further processing or be compacted to tablets
with only a small amount of tabletting aids.
[0049] The water-soluble polymer comprised in the dosage form is a
polymer that preferably has an apparent viscosity, when dissolved
at 20.degree. C. in an aqueous solution at 2% (w/v), of about 1 to
about 5000 mPas. more preferably of about 1 to about 700 mPas, and
most preferred of about 5 to about 100 mPas. Water-soluble polymers
suitable for use in the present invention include for example, but
are not limited thereto:
[0050] homopolymers and copolymers of N-vinyl lactams, especially
homopolymers and copolymers of N-vinyl pyrrolidone, e.g.
polyvinylpyrrolidone (PVP), copolymers of N-vinyl pyrrolidone and
vinyl acetate or vinyl propionate,
[0051] cellulose esters and cellulose ethers, in particular
methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in
particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in
particular hydroxypropylmethylcellulose, cellulose phthalates or
succinates, in particular cellulose acetate phthalate and
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate or
hydroxypropylmethylcellulose acetate succinate;
[0052] high molecular polyalkylene oxides such as polyethylene
oxide and polypropylene oxide and copolymers of ethylene oxide and
propylene oxide,
[0053] polyacrylates and polymethacrylates such as methacrylic
acid/ethyl acrylate copolymers, methacrylic acid/methyl
methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl
methacrylate copolymers, poly(hydroxyalkyl acrylates),
poly(hydroxyalkyl methacrylates),
[0054] polyacrylamides,
[0055] vinyl acetate polymers such as copolymers of vinyl acetate
and crotonic acid, partially hydrolyzed polyvinyl acetate (also
referred to as partially saponified "polyvinyl alcohol"),
[0056] polyvinyl alcohol,
[0057] oligo- and polysaccharides such as carrageenans,
galactomannans and xanthan gum, or mixtures of one or more
thereof.
[0058] Of these, homopolymers or copolymers of N-vinyl pyrrolidone,
in particular a copolymer of N-vinyl pyrrolidone and vinyl acetate,
are preferred. A particularly preferred polymer is a copolymer of
about 60% by weight of the copolymer, N-vinyl pyrrolidone and about
40% by weight of the copolymer, vinyl acetate.
[0059] The dosage forms of the invention may contain at least one
conventional additive, such as flow regulators, lubricants, bulking
agents (fillers) and disintegrants. In general, the additive is
contained in an amount of about 0.01 to about 15% by weight
relative to the weight of the dosage form.
[0060] Various methods can be used for manufacturing the solid
dosage forms according to the invention. These methods comprise the
preparation of a solid solution of the HIV protease inhibitor or
the combination of HIV protease inhibitors in a matrix of the
water-soluble polymer and the surfactant, and shaping into the
required tablet form. Alternatively, the solid solution product may
be subdivided to granules, e.g. by grinding or milling, and the
granules may subsequently be compacted to tablets.
[0061] Various techniques exist for preparing solid solutions
including melt-extrusion, spray-drying and solution-evaporation
with melt-extrusion being preferred.
[0062] The melt-extrusion process comprises the steps of preparing
a homogeneous melt of the HIV protease inhibitor or the combination
of HIV protease inhibitors, the water-soluble polymer and the
surfactant, and cooling the melt until it solidifies. "Melting"
means a transition into a liquid or rubbery state in which it is
possible for one component to get embedded homogeneously in the
other. Typically, one component will melt and the other components
will dissolve in the melt thus forming a solution. Melting usually
involves heating above the softening point of the water-soluble
polymer. The preparation of the melt can take place in a variety of
ways. The mixing of the components can take place before, during or
after the formation of the melt. For example, the components can be
mixed first and then melted or be simultaneously mixed and melted.
Usually, the melt is homogenized in order to disperse the active
ingredients efficiently. Also, it may be convenient first to melt
the water-soluble polymer and then to mix in and homogenize the
active ingredients.
[0063] Usually, the melt temperature is in the range of about 70 to
about 250.degree. C., preferably from about 80 to about 180.degree.
C., most preferred from about 100 to about 140.degree. C.
[0064] The active ingredients can be employed as such or as a
solution or dispersion in a suitable solvent such as alcohols,
aliphatic hydrocarbons or esters. Another solvent which can be used
is liquid carbon dioxide. The solvent is removed, e.g. evaporated,
upon preparation of the melt.
[0065] Various additives may be included in the melt, for example
flow regulators such as colloidal silica; lubricants, fillers,
disintegrants, plasticizers, stabilizers such as antioxidants,
light stabilizers, radical scavengers, stabilizers against
microbial attack.
[0066] The melting and/or mixing takes place in an apparatus
customary for this purpose. Particularly suitable ones are
extruders or kneaders. Suitable extruders include single screw
extruders, intermeshing screw extruders or else multiscrew
extruders, preferably twin screw extruders, which can be corotating
or counterrotating and, optionally, be equipped with kneading
disks. It will be appreciated that the working temperatures will
also be determined by the kind of extruder or the kind of
configuration within the extruder that is used. Part of the energy
needed to melt, mix and dissolve the components in the extruder can
be provided by heating elements. However, the friction and shearing
of the material in the extruder may also provide a substantial
amount of energy to the mixture and aid in the formation of a
homogeneous melt of the components.
[0067] The melt ranges from pasty to viscous. Shaping of the
extrudate conveniently is carried out by a calender with two
counter-rotating rollers with mutually matching depressions on
their surface. A broad range of tablet forms can be attained by
using rollers with different forms of depressions. Alternatively,
the extrudate is cut into pieces, either before (hot-cut) or after
solidification (cold-cut).
[0068] Optionally, the resulting solid solution product is milled
or ground to granules. The granules may then be compacted.
Compacting means a process whereby a powder mass comprising the
granules is densified under high pressure in order to obtain a
compact with low porosity, e.g. a tablet. Compression of the powder
mass is usually done in a tablet press, more specifically in a
steel die between two moving punches. Where a solid dosage form of
the invention comprises a combination of more than one HIV protease
inhibitor (or a combination of an HIV protease inhibitor with one
or more other active ingredients) it is of course possible to
separately prepare solid solution products of the individual active
ingredients and to blend the milled or ground products before
compacting.
[0069] At least one additive selected from flow regulators,
disintegrants, bulking agents (fillers) and lubricants is
preferably used in compacting the granules. Disintegrants promote a
rapid disintegration of the compact in the stomach and keeps the
granules which are liberated separate from one another. Suitable
disintegrants are crosslinked polymers such as crosslinked
polyvinyl pyrrolidone and crosslinked sodium
carboxymethylcellulose. Suitable bulking agents (also referred to
as "fillers") are selected from lactose, calcium hydrogenphosphate,
microcrystalline cellulose (Avicell.RTM.), silicates, in particular
silicium dioxide, magnesium oxide, talc, potato or corn starch,
isomalt, polyvinyl alcohol.
[0070] Suitable flow regulators are selected from highly dispersed
silica (Aerosil.RTM.), and animal or vegetable fats or waxes.
[0071] A lubricant is preferably used in compacting the granules.
Suitable lubricants are selected from polyethylene glycol (e.g.,
having a Mw of from 1000 to 6000), magnesium and calcium stearates,
sodium stearyl fumarate, and the like.
[0072] Various other additives may be used, for example dyes such
as azo dyes, organic or inorganic pigments such as aluminium oxide
or titanium dioxide, or dyes of natural origin; stabilizers such as
antioxidants, light stabilizers, radical scavengers, stabilizers
against microbial attack.
[0073] Dosage forms according to the invention may be provided as
dosage forms consisting of several layers, for example laminated or
multilayer tablets. They can be in open or closed form. "Closed
dosage forms" are those in which one layer is completely surrounded
by at least one other layer. Multilayer forms have the advantage
that two active ingredients which are incompatible with one another
can be processed, or that the release characteristics of the active
ingredient(s) can be controlled. For example, it is possible to
provide an initial dose by including an active ingredient in one of
the outer layers, and a maintenance dose by including the active
ingredient in the inner layer(s). Multilayer tablets types may be
produced by compressing two or more layers of granules.
Alternatively, multilayer dosage forms may be produced by a process
known as "coextrusion". In essence, the process comprises
preperation of at least two different melt compositions as
explained above, and passing these molten compositions into a joint
coextrusion die. The shape of the coextrusion die depends on the
required drug form. For example, dies with a plain die gap, called
slot dies, and dies with an annular slit are suitable.
[0074] In order to facilitate the intake of such a dosage form by a
mammal, it is advantageous to give the dosage form an appropriate
shape. Large tablets that can be swallowed comfortably are
therefore preferably elongated rather than round in shape.
[0075] A film coat on the tablet further contributes to the ease
with which it can be swallowed. A film coat also improves taste and
provides an elegant appearance. If desired, the film-coat may be an
enteric coat. The film-coat usually includes a polymeric
film-forming material such as hydroxypropyl methylcellulose,
hydroxypropylcellulose, and acrylate or methacrylate copolymers.
Besides a film-forming polymer, the film-coat may further comprise
a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a
Tween.RTM. type, and optionally a pigment, e.g. titanium dioxide or
iron oxides. The film-coating may also comprise talc as
anti-adhesive. The film coat usually accounts for less than about
5% by weight of the dosage form.
[0076] The exact dose and frequency of administration depends on
the particular condition being treated, the age, weight and general
physical condition of the particular patient as well as other
medication the individual may be taking, as is well known to those
skilled in the art.
[0077] Exemplary compositions of the present invention for combined
administration of ritonavir/lopinavir are shown below in Table 1,
and the values are % by weight.
TABLE-US-00001 TABLE 1 Ritonavir 18-22.5 in 4.17 4.17 Lopinavir
total 16.67 16.67 Copovidone (N- 65-75 71.16 70.12 vinyl
pyrrolidone/vinyl acetate copolymer 60:40) Span 20 (Sorbitan 4-10
7.0 5.02 monolaurate) Cremophor RH40 0-10 -- 3.02
(polyoxyethyleneglycerol oxystearate) Colloidal silica 0-3 1.0
1.0
[0078] Exemplary compositions of the invention for administration
of ritonavir only are shown below in Table 2. The values are % by
weight.
TABLE-US-00002 Ritonavir .sup. 18-22.5 20.8 Lopinavir -- --
Copovidone (N- 60-75 63.15 vinyl pyrrolidone/vinyl acetate
copolymer 60:40) Span 20 (Sorbitan 5-15 in -- monolaurate) total
Cremophor RH40 10.00 (polyoxyethyleneglycerol oxystearate) PEG 6000
0-8 5.00 Colloidal silica 0-3 1.04
[0079] The above compositions are processed by melt extrusion. The
resulting extrudates may be used as such or milled and compressed
into tablets, preferably by the use of suitable tabletting aids
such as sodium stearyl fumarate, colloidal silica, lactose,
isomalt, calcium silicate, and magnesium stearate, cellulose or
calcium hydrogenphosphate.
[0080] The following examples will serve to further illustrate the
invention without limiting it.
[0081] Protocol for the Oral Bioavailability Studies
[0082] Dogs (beagle dogs, mixed sexes, weighing approximately 10
kg) received a balanced diet with 27% fat and were permitted water
ad libitum. Each dog received a 100 .mu.g/kg subcutaneous dose of
histamine approximately 30 minutes prior to dosing. A single dose
corresponding to about 200 mg lopinavir, about 50 mg ritonavir, or
about 200 mg lopinavir and about 50 mg ritonavir, respectively, was
administered to each dog. The dose was followed by approximately 10
milliliters of water. Blood samples were obtained from each animal
prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12 and
24 hours after drug administration. The plasma was separated from
the red cells by centrifugation and frozen (-30.degree. C.) until
analysis. Concentrations of HIV protease inhibitors were determined
by reverse phase HPLC with low wavelength UV detection following
liquid-liquid extraction of the plasma samples. The area under the
curve (AUC) was calculated by the trapezoidal method over the time
course of the study. Each dosage form was evaluated in a group
containing 8 dogs; the values reported are averages for each group
of dogs.
COMPARATIVE EXAMPLE
[0083] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 78.17 parts by weight) was mixed with ritonavir (4.16 parts
by weight), lopinavir (16.67 parts by weight) and colloidal silica
(1.0 part by weight). The powdery mixture was then fed into a
twin-screw extruder (screw diameter 18 mm) at a rate of 2.0 kg/h
and a melt temperature of 133.degree. C. The clear, fully
transparent melt was fed to a calender with two counter-rotating
rollers having mutually matching cavities on their surfaces.
Tablets of 1080 mg were thus obtained. DSC and WAXS analysis did
not reveal any evidence of crystalline drug material in the
formulation.
[0084] The dose-adjusted AUC in dogs was 0.52 .mu.gh/ml/100 mg for
ritonavir and 4.54 .mu.gh/ml/100 mg for lopinavir. This example
shows that solid solutions of HIV protease inhibitors without added
surfactant yield a very poor bioavailabilty.
Example 1
[0085] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 68.17 parts by weight) was blended with Cremophor RH40
(polyoxyethyleneglycerol oxystearate; 10.00 parts by weight) in a
Diosna high-shear mixer. The resulting granules were mixed with
ritonavir (4.17 parts by weight), lopinavir (16.67 parts by weight)
and colloidal silica (1.00 parts by weight). The powdery mixture
was then fed into a Leistritz Micro 18 twin-screw extruder at a
rate of 2.3 kg/h and a melt temperature of 126.degree. C. The
extrudate was cut into pieces and allowed to solidify. The extruded
pieces were milled using a high impact universal mill. The milled
material (86.49 parts by weight) was blended in a bin blender with
lactose monohydrate (6.00 parts by weight), crosslinked PVP (6.00
parts by weight), colloidal silica (1.00 part by weight) and
magnesium stearate (0.51 parts by weight). The powdery blend was
compressed to tablets of 1378.0 mg on a Fette E 1 single punch
tablet press. The tablets were then film-coated in a coating pan by
spraying an aqueous dispersion for film coating (Opadry, available
from Colorcon) at a temperature of 60.degree. C.
[0086] The dose-adjusted AUC in dogs was 0.60 .mu.gh/ml/100 mg for
ritonavir and 7.43 .mu.gh/ml/100 mg for lopinavir. This example
shows that inclusion of a surfactant into solid solutions of HIV
protease inhibitors improves the bioavailabilty attained.
Example 2
[0087] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 853.8 parts by weight) was blended with Span 20 (Sorbitan
monolaurate; 83.9 parts by weight) in a Diosna high-shear mixer.
The resulting granules were mixed with ritonavir (50 parts by
weight), lopinavir (200 parts by weight) and colloidal silica (12
parts by weight). The powdery mixture was then fed into a
twin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h
and a melt temperature of 119.degree. C. The extrudate was fed to a
calender with two counter-rotating rollers having mutually matching
cavities on their surfaces. Tablets of 1120 mg were thus
obtained.
[0088] The dose-adjusted AUC in dogs was 10.88 .mu.gh/ml/100 mg for
ritonavir and 51.2 .mu.gh/ml/100 mg for lopinavir. This example
shows that inclusion of a surfactant having an HLB of 4 to 10 into
solid solutions of HIV protease inhibitors markedly improves the
bioavailability attained.
Example 3
[0089] Example 2 was repeated, however, the extrudate was cut into
pieces and allowed to solidify. The extruded pieces were milled to
a particle size of about 250 .mu.m, using a high impact universal
mill. The milled material was blended in a bin blender with sodium
stearyl fiumarate (12.3 parts by weight) and colloidal silica (8.0
parts by weight) for 20 min. The powdery blend was compressed on a
rotary tablet machine with 3 punches (6500 tablets/h). The tablets
were then film-coated in a coating pan by spraying an aqueous
dispersion for film coating (Opadry) at a temperature of 60.degree.
C.
[0090] The dose-adjusted AUC in dogs was 14.24 .mu.gh/ml/100 mg for
ritonavir and 52.2 .mu.gh/ml/100 mg for lopinavir.
Example 4
[0091] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 841.3 parts by weight) was blended with Cremophor RH40
(polyoxyethyleneglycerol oxystearate; 36.2 parts by weight), Span
20 (Sorbitan monolaurate; 60.2 parts by weight) in a Diosna
high-shear mixer. The resulting granules were mixed with ritonavir
(50 parts by weight), lopinavir (200 parts by weight) and colloidal
silica (12 parts by weight). The powdery mixture was then fed into
a twin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h
and a melt temperature of 114.degree. C. The extrudate was fed to a
calender with two counter-rotating rollers having mutually matching
cavities on their surfaces. Tablets of 1120 mg were thus
obtained.
[0092] The dose-adjusted AUC in dogs was 10.96 .mu.gh/ml/100 mg for
ritonavir and 46.5 .mu.gh/ml/100 mg for lopinavir. This example
shows that a combination of a surfactant having an HLB of 4 to 10
and a further surfactant can successfully be used.
Example 5
[0093] Example 4 was repeated, however, the extrudate was cut into
pieces and allowed to solidify. The extruded pieces were milled to
a particle size of about 250 .mu.m, using a high impact universal
mill. The milled material was blended in a bin blender with sodium
stearylfumarate (13.9 parts by weight), colloidal silica (7.0 parts
by weight), isomalt DC100 (159.4 parts by weight) and calcium
silicate (7.0 parts by weight) for 20 min. The blend was compressed
and film-coated as described in example 1.
[0094] The dose-adjusted AUC in dogs was 10.38 .mu.gh/ml/100 mg for
ritonavir and 42.7 .mu.gh/ml/100 mg for lopinavir.
Example 6
[0095] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 683.3 parts by weight) was blended with Span 40 (sorbitan
monopalmitate; 67.2 parts by weight) in a Diosna high-shear mixer.
The resulting granules were mixed with lopinavir (200 parts by
weight) and colloidal silica (9.6 parts by weight). The powdery
mixture was then fed into a twin-screw extruder (screw diameter 18
mm) at a rate of 2.1 kg/h and a melt temperature of 119.degree. C.
The extrudate was cut into pieces and allowed to solidify. The
extruded pieces were milled using a high impact universal mill. The
milled material was blended in a bin blender with sodium
stearylfumarate (7.9 parts by weight), colloidal silica (11.3 parts
by weight), isomalt DC100 (129.1 parts by weight) and sodium
dodecyl sulfate (15.6 parts by weight). The blend was compressed
and film-coated as described in example 1.
[0096] Tablets corresponding to 200 mg lopinavir were
coadministered to dogs together with 50 mg ritonavir. The
dose-adjusted AUC of lopinavir was 38.8 .mu.gh/ml/100 mg.
Example 7
[0097] Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer
60:40; 151.5 parts by weight) was blended with Cremophor RH40 (24
parts by weight) and PEG 6000 (12 parts by weight) in a Diosna
high-shear mixer. The resulting granules were mixed with ritonavir
(50 parts by weight) and colloidal silica (2.4 parts by weight).
The powdery mixture was then fed into a twin-screw extruder and was
melt-extruded. The extrudate was cut into pieces and allowed to
solidify. The extruded pieces were milled using a high impact
universal mill. The milled material was blended in a bin blender
with colloidal silica (1.4 parts by weight), isomalt DC100 (31.9
parts by weight) and calcium silicate (4.2 parts by weight). The
blend was compressed and film-coated as described in example 1.
[0098] The dose-adjusted AUC in dogs was 9.98 .mu.gh/ml/100 mg.
* * * * *